Evaluating thyroid transport protein binding activity and structure–activity relationship of hydroxylated polybrominated diphenyl ethers using three-dimensional quantitative structure–activity relationship models
Polybrominated diphenyl ethers (PBDEs) have become globally significant environmental pollutants because of their persistence, bioaccumulative nature, and potential toxicity. Hydroxylated PBDEs (OH-PBDEs) are environmental thyroid-disrupting chemicals. Their toxicity primarily manifests through competitive binding with thyroid hormone transport proteins, including transthyretin (TTR) and thyroxine-binding globulin (TBG), disrupting the endocrine system. In this study, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was developed to predict the binding activity of OH-PBDEs. Binding activity data for 14 representative OH-PBDEs (containing 1–6 bromine atoms) against TTR and TBG were selected. 3D-QSAR models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For TTR, the CoMFA model exhibited the best predictive capability and robustness, with a cross-validated coefficient of Q2 = 0.611, a fitted correlation coefficient of R2 = 0.999, and a standard error of estimate (SEE) of 0.014. The CoMSIA model for TTR yielded Q2 = 0.502, R2 = 0.999, and SEE = 0.017. For TBG, all models yielded Q2 < 0.5. This indicates insufficient predictive ability and was therefore not used for subsequent prediction. Field contribution analysis identified electrostatic field as the predominant factor governing binding activity (contribution rate: 65.4% in CoMFA). Using the optimal TTR-CoMFA model, the activities of 40 OH-PBDE isomers were predicted. T3 and T4 were used separately as endogenous reference ligands (predicted pIC50 = 7.573 and 7.921, respectively) and were not included in the OH-PBDE ranking. Among the predicted OH-PBDEs, OH-BDE-085 and OH-BDE-154 showed higher activity than T4, whereas OH-BDE-003 and OH-BDE-007 showed lower activity than T3. The remaining OH-PBDEs fell between T3 and T4. These results indicate that, within the range of 1–6 bromine atoms and under specific substitution patterns, increasing bromination generally enhances TTR binding activity. This study provides an efficient computational tool for the rapid screening of high-risk OH-PBDE congeners, establishing a scientific basis for environmental health risk assessment.
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